Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans

Hasse Walum*†‡, Lars Westberg†§, Susanne Henningsson§, Jenae M. Neiderhiser¶, David Reissʈ, Wilmar Igl*, Jody M. Ganiban**, Erica L. Spotts††, Nancy L. Pedersen*, Elias Eriksson§, and Paul Lichtenstein*

*Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Box 281, S-171 77 Stockholm, Sweden; §Department of Pharmacology, Institute of Neuroscience and Physiology, University of Gothenburg, Box 431, S 405 30 Gothenburg, Sweden; ¶Department of Psychology, Pennsylvania State University, University Park, PA 16802; ʈYale Child Study Center, Yale University, New Haven, CT 06520; **Department of Psychology, The George Washington University, Building GG 2125 G St NW, Washington, DC 20052; and ††Behavioral and Social Research Program, National Institute on Aging, Bethesda, MD 20892-9205

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved July 14, 2008 (received for review March 28, 2008) Pair-bonding has been suggested to be a critical factor in the prairie vole avpr1a affects brain expression of the gene and alters evolutionary development of the social brain. The brain neuropep- intraspecific variation in partner preference (8). tide arginine vasopressin (AVP) exerts an important influence on Human AVPR1A is situated on chromosome 12q14–15 (9). pair-bonding behavior in voles. There is a strong association Whereas there is no sequence in the human AVPR1A 5Ј flanking between a polymorphic repeat sequence in the 5؅ flanking region region homologous to the one found in prairie voles, humans do of the gene (avpr1a) encoding one of the AVP receptor subtypes have three repetitive sequences in this region that are polymor- (V1aR), and proneness for monogamous behavior in males of this phic: A (GT)25 dinucleotide repeat, a complex (CT)4-TT-(CT)8- species. It is not yet known whether similar mechanisms are (GT)24 repeat (RS3), and a (GATA)14 tetranucleotide repeat important also for human pair-bonding. Here, we report an asso- (RS1) (10). Although as yet not consistently replicated, previous ciation between one of the human AVPR1A repeat polymorphisms studies have revealed associations between AVPR1A repeat (RS3) and traits reflecting pair-bonding behavior in men, including polymorphisms and autism (11–13), age at first sexual inter- partner bonding, perceived marital problems, and marital status, course (14), and altruism (15), suggesting that these repetitive and show that the RS3 genotype of the males also affects marital sequences may have an impact on human social behavior. The aim of this study was to investigate whether variability in quality as perceived by their spouses. These results suggest an Ј association between a single gene and pair-bonding behavior in the 5 flanking region of AVPR1A affects pair-bonding behavior in humans as it does in prairie voles. To this end, the three repeat humans, and indicate that the well characterized influence of AVP polymorphisms of the AVPR1A were genotyped in adult men and on pair-bonding in voles may be of relevance also for humans. women from the Twin and Offspring Study in Sweden (TOSS), comprised of 552 same-sex twin-pairs and their spouses/partners monogamy ͉ neuropeptide ͉ polymorphism ͉ social behavior (16). All subjects were assessed with respect to various indices of the quality of the marital relationship, including a new scale–the rimate social organization is often characterized by bonded Partner Bonding Scale (PBS)–which is comprised of items that Prelationships, and recent analyses suggest that it may have been correspond to the behavioral patterns observed when measuring the particular demands for pair-bonding behavior that triggered the features of pair-bonds among nonhuman primates. evolutionary development of the primate social brain (1). The brain neuropeptide arginine vasopressin (AVP), acting through the re- Results NEUROSCIENCE ceptor subtype V1aR, plays a key role in the regulation of pair- The allele and genotype distributions of the three repeat poly- bonding behavior in male rodents, as revealed by a series of elegant morphisms (RS1, RS3, and GT25) were similar to what has been studies on closely related vole species, i.e., montane voles (Microtus reported in previous studies (10, 11, 17) and did not deviate from montanus), meadow voles (Microtus pennsylvanicus), and prairie Hardy–Weinberg equilibrium. After correction for multiple voles (Microtus ochrogaster) (2). In prairie voles, which in contrast tests, there was a significant global P value for an association to montane and meadow voles are socially monogamous and highly between the RS3-repeat polymorphism and the outcome of the social, pair-bond formation and related behaviors are facilitated by PBS for men (P Ͻ 0.01 after a Bonferroni correction of the six AVP and prevented by a V1aR antagonist (3). Supporting the tests), but not for women (Table 1). No associations were found theory that the striking difference in pair-bonding between mo- for the other AVPR1A polymorphisms. When comparing the nogamous and nonmonogamous voles is related to the influence of mean scores of the PBS for each RS3 allele (Table 2), this value AVP on this behavior, the neuroanatomical distribution of V1aR was found to be significantly lower for men carrying allele 334 than for those not carrying this allele (F1,130 ϭ 16.35, P Ͻ 0.0001, differs considerably between these vole species (4) and is associated ϭ Ͻ with sexual and social fidelity among prairie voles (5). Moreover, d 0.27; P 0.001 after correction for the 11 tests). In addition, partner preference is enhanced in the nonmonogamous meadow

vole when the V1aR density is increased in relevant brain areas by Author contributions: H.W., L.W., S.H., J.M.N., D.R., J.M.G., E.L.S., N.L.P., E.E., and P.L. using viral vector gene transfer (6). Although there are no major designed research; W.I. contributed new reagents/analytic tools; H.W. analyzed data; and differences in the coding sequence of the gene encoding V1aR H.W. and L.W. wrote the paper. (avpr1a) between prairie, montane or meadow voles, the former The authors declare no conflict of interest. species displays a 428-base pair sequence in the 5Ј flanking region This article is a PNAS Direct Submission. that is not found in the latter two species. When the avpr1a of the †H.W. and L.W. contributed equally to this work. prairie vole, including the sequence in the 5Ј region, is transgenically ‡To whom correspondence should be addressed. E-mail: [email protected]. inserted into the nonmonogamous species mouse (7), more pro- This article contains supporting information online at www.pnas.org/cgi/content/full/ nounced social behavior, similar to that displayed by prairie voles, 0803081105/DCSupplemental. is generated. Furthermore, variation in the 5Ј flanking region of © 2008 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0803081105 PNAS ͉ September 16, 2008 ͉ vol. 105 ͉ no. 37 ͉ 14153–14156 Downloaded by guest on September 26, 2021 Table 1. Association between the different microsatellite Next we investigated whether the genotype of the men influ- polymorphisms in the AVPR1A 5؅ flanking region and the enced marital quality as perceived by their spouses. For this Partner Bonding Scale purpose, we used the Dyadic Consensus, Dyadic Satisfaction, Men Women Dyadic Cohesion, and Affectional Expression subscales from the Dyadic Adjustment Scale (DAS) (19), measures frequently used Repeat df F P Repeat df F P to evaluate the quality of marital relationships. As hypothesized, the marital quality, as perceived by the wives, was significantly GT25 21, 148 0.39 0.99 GT25 18, 138 1.05 0.41 RS1 16, 187 1.03 0.43 RS1 15, 197 0.99 0.46 associated with the RS3 genotype of their husbands. Women RS3 19, 157 2.48 0.001 RS3 21, 166 1.19 0.27 married to men with one or two 334 alleles scored significantly lower on the Affection Expression, Dyadic Consensus, and Only genotypes for which n Ͼ 10 were included in the analyses. Dyadic Cohesion subscales than did women married to men without the 334 allele (Table 4), and effect sizes ranged from d ϭ 0.14–0.20. However, the difference between carriers of one or a dose-dependent effect of the number of 334 alleles on the PBS two 334 alleles that was observed when analyzing the outcome score (Table 3) was found, with carriers of two alleles showing of the PBS for the men was not found for the rating conducted ϭ the lowest scores. The size of these effects were d 0.27 between by their spouses. When the women’s ratings were adjusted for the ϭ men not carrying any 334 allele and 334 heterozygotes, and d husbands’ scores on the PBS, a considerable change of regression 0.38 between men not carrying any 334 allele and 334 homozy- estimates (␤) was obtained; suggesting that the behaviors as- gotes. After Bonferroni correction, no RS3 allele other than the sessed by the PBS mediate the association of the 334 allele with 334 allele displayed a significant association with scores on the PBS. the wives’ reported quality of the marital relationship. The association between the RS3 polymorphism and the scores of the PBS prompted us to examine to what extent an Discussion influence of this polymorphism on marital quality could be The results from the current study suggest an association be- detected when using other measures than the PBS. To this end, tween a AVPR1A polymorphism and human pair-bonding be- we first assessed whether carriers of allele 334 reported more havior possibly analogous to that reported for voles (8). One of marital problems than men without it, by using an item collected the most common RS3 alleles, the allele 334, was associated with from a life event questionnaire based on the Social Readjust- perceived partner bonding in men as assessed by using the PBS. ment Rating Scale (18), asking whether the male subjects had This association could be detected also by assessing marital experienced marital crisis or threat of divorce during the last problems and marital status in men, and the perception of the year. In line with our assumption, carriers of the RS3 allele 334 quality of the marital relationship expressed by their spouses. responded affirmatively more often to this question (Table 3). That an association between the studied gene and items reflect- Fifteen percent of the men carrying no 334 allele reported ing pair-bonding was found only in men is consistent with the fact marital crisis, whereas 34% of the men carrying two copies of this that the influence of vasopressin on social behavior is more allele reported marital crisis, suggesting that being homozygous prominent in male than in female voles (20). for the 334 allele doubles the risk of marital crisis compared with Although the functional importance of the RS3 polymorphism having no 334 allele. of the AVPR1A remains to be clarified, an association between The validity analysis, reported in the Materials and Methods the length of the RS3 repeat and the amount of hippocampal section, showed that unmarried individuals scored significantly mRNA in human postmortem tissue has been reported (15). lower than married subjects on the PBS. Thus, we hypothesized Moreover, a recent study in healthy subjects suggests that the 334 allele is associated with increased activation of amygdala, a brain that men carrying the RS3 allele 334 more often were involved region known to be of importance for pair-bonding behavior in a relationship without being married. The allele 334 was (17). The conclusion of our study (that the 334 allele of the RS3 indeed associated with marital status (Table 3); the frequency of polymorphism influences brain function) is well in line with nonmarried men being higher among 334 homozygotes (32%) previous observations. than among men with no 334 alleles (17%). The possible influence of AVP on social interactions has led researchers to suggest an involvement of this transmitter in Table 2. Association between different RS3 alleles and the conditions characterized by social deficits, for example, autism Partner Bonding Scale in men and autism-related conditions. This theory has gained support from studies assessing the possible association between AVPR1A Allele Freq Percent Mean df F P and risk for autism (11–13) and other traits related to interper- 320 21 2.3 48.8 (6.21) 1, 12 1.52 0.24 sonal relationships (15). Although it is difficult to compare the 330 92 9.9 47.6 (7.18) 1, 37 0.21 0.65 results of these studies to those of our study, it is of interest to 332 128 13.8 47.5 (6.45) 1, 50 0.06 0.81 note that one of these studies suggests the 334 allele to be 334 371 40.0 46.2 (6.23) 1, 130 16.35 Ͻ0.0001 over-transmitted to subjects with autism (11). The observation 336 359 38.7 47.6 (6.35) 1, 133 1.51 0.22 that a gene variant, which according to our data, is negatively 338 170 18.3 48.3 (6.21) 1, 77 4.73 0.03 associated with the ability to interact within a relationship, may 340 263 28.4 47.5 (6.56) 1, 106 0.40 0.53 enhance the risk for a condition characterized by impaired social 342 30 3.2 47.0 (4.49) 1, 12 0.05 0.82 impairments of social relatedness and communication is obvi- 344 23 2.5 45.6 (6.43) 1, 8 1.64 0.24 ously noteworthy. 346 126 13.6 46.7 (6.87) 1, 60 1.30 0.26 The effect size (d) for the influence of the studied allele on 348 37 4.0 47.9 (8.47) 1, 16 0.36 0.55 PBS scores when comparing men who carry one or two 334 alleles with those who do not carry any was 0.27. This is Analyses were performed by comparing individuals carrying one or two of comparable with what has been reported in large metaanalyses an allele with individuals not carrying this allele. Freq, Frequency, denoting of the association between a DRD4 polymorphism and the number of individuals carrying one or two of the given allele. Mean, Mean ϭ value for the Partner Bonding Scale (standard deviation within brackets). Only personality trait novelty seeking (d 0.32) (19) and that between alleles for which n Ͼ 10 were included in the analyses. Six alleles were thereby a serotonin transporter polymorphism and neuroticism (d ϭ excluded. 0.23) (20), despite the fact that the outcome of the PBS, unlike

14154 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0803081105 Walum et al. Downloaded by guest on September 26, 2021 Table 3. Effect of 0, 1 or 2 334 alleles on male reports on the Partner Bonding Scale, marital crisis, and marital status Number of 334 alleles

Measure 012df F P

Mean score for the Partner Bonding Scale in the three groups Partner Bonding Scale 48.0 (6.50) 46.3 (6.16) 45.5 (6.71) 2, 143 8.40 0.0004

Frequency and column-wise percentage of subjects reporting marital crisis/threat of divorce in the three groups Have you experienced marital crisis or threat of divorce during the last year? No 469 (85%) 277 (84%) 27 (66%) 2, 143 5.00 0.008 Yes 81 (15%) 51 (16%) 14 (34%)

Frequency and column-wise percentage of subjects being married or cohabiting in the three groups Marital status Married 457 (83%) 275 (84%) 28 (68%) 2, 143 4.36 0.01 Cohabiting 96 (17%) 52 (16%) 13 (32%)

Values for the Partner Bonding Scale are means with standard deviation in brackets.

novelty seeking and neuroticism to some extent is influenced not this study clearly does not mean that this polymorphism may only by the informant but also by his/her partner. serve as a predictor of human pair-bonding behavior on the It is notable that an association was found between the RS3 individual level. However, by demonstrating a modest but sig- repeat of the AVPR1A and indices of pair-bonding behavior in nificant influence of this gene on the studied behavior on the a cohort in which all subjects had been married or cohabiting for group level, we have provided support for the assumption that at least five years. Tentatively, such an association would be even previous studies on the influence of the gene coding for V1aR on stronger in a population also comprising subjects not involved in pair-bonding in voles are probably of relevance also for humans. any long-term romantic relationships. It would also be of im- portance to assess the possible influence of this polymorphism Materials and Methods on measures of pair-bonding that are more objective than Subjects. The study consisted of 552 twin pairs and their spouses from the self-report, such as proneness for cohabiting versus living alone, second cohort of the Twin and Offspring Study in Sweden (TOSS), a two-cohort marriage, and divorce. However, of some interest in this context study of twin parents, one adolescent child, and the spouse/partner, for which detailed measures of parent-child relationships, marital relationships, person- is our observation that men that were homozygous for the 334 ality, attachment style, and the mental health of all study participants were allele were more likely to be unmarried than other men, despite collected (16). Participants were mostly middle class and born between 1944 the fact that the cohabiting individuals in our sample had been and 1971. Consistent with the population of Sweden, the vast majority were in a relationship persisting for at least five years and that in the Caucasian. A more detailed description of the sample is available in a previous vast majority of all of these couples, both individuals were article by Neiderhiser and coworkers (16). The same-sex twins included in the biological parents to a adolescent child, ranging in age from 11- study were required to have a relationship of at least five years with their to 22-years-old. This finding is in line with the observation that partner; whereas 82% were married, 18% were cohabiting but unmarried. For unmarried men displayed lower scores on the PBS (see Materials simplicity, both married and unmarried cohabiting individuals are referred to as ‘‘husband,’’ ‘‘wife,’’ or ‘‘spouse.’’ The twins and their spouses were first sent and Methods) and may tentatively reflect a lower degree of a questionnaire that was followed by a home visit, during which additional NEUROSCIENCE commitment in those being unmarried. questionnaires were administered. DNA was extracted from mouthwash sam- The relatively small effect size of the AVPR1A polymorphism ples that were collected by using a DNA self-collection kit. Zygosity was on traits tentatively reflecting pair-bonding in males observed in determined primarily by genotyping. There were 238 monozygotic (MZ) pairs

Table 4. Association between 334 alleles in men and their wives’ reports of marital qualities One or two 334 No 334 Quality (mean) (mean) ␤ df F P

Affectional expression Unadjusted 18.0 (2.99) 17.4 (2.92) Ϫ0.64 1, 113 10.08 0.002 Adjusted — — Ϫ0.39 1, 111 4.30 0.04

Dyadic consensus Unadjusted 65.4 (8.11) 63.9 (8.57) Ϫ1.46 1, 117 6.92 0.01 Adjusted — — Ϫ0.82 1, 115 2.46 0.12

Dyadic cohesion Unadjusted 19.5 (4.34) 18.9 (4.10) Ϫ0.60 1, 116 4.27 0.04 Adjusted — — Ϫ0.20 1, 114 0.53 0.47

Dyadic satisfaction Unadjusted 43.3 (3.14) 43.2 (2.92) Ϫ0.12 1, 111 0.49 0.49

Mean, Mean value on the outcome for the different DAS Scales for wives with standard deviation within brackets. Adjusted, Analysis with the Partner Bonding Scale included as a covariate. The category of subjects not carrying any 334 allele was used as reference group when constructing the regression estimates (␤ ). Analyses of adjusted values were only performed for the scales that were significantly associated with the 334 allele in the unadjusted analysis.

Walum et al. PNAS ͉ September 16, 2008 ͉ vol. 105 ͉ no. 37 ͉ 14155 Downloaded by guest on September 26, 2021 and 314 dizygotic (DZ) pairs. In total, 2,186 adult individuals were included in By using the fact that the studied population comprised twin pairs, we finally the study, of which 1,899 provided usable DNA samples. made an assessment of the heritability of this parameter in the studied cohort. The intraclass correlation for the scale was 0.27 for monozygotic (MZ) and 0.03 Partner Bonding Scale. The pair bond is a critical element in the study of the for dizygotic (DZ) males. The corresponding figures were 0.47 and 0.33 for 2 ϭ Ϫ evolution of primate social organization (21). Pair bonds among nonhuman females. Heritability according to Falconer’s formula (h 2(rMZ rDZ)) (28) primates are generally assessed by measures of partner specific affiliative was 0.27 for men and 0.28 for women, similar to what has been observed for interaction, proximity, and reciprocity between two individuals (22–24). Fur- marital satisfaction (29) and divorce (30). thermore, the strength and stability of the bond is related to its persistence through time (25). In accordance with the behavioral domains observed when Microsatellite Genotyping. The GT25 repeat polymorphism was amplified with studying pair-bonding among nonhuman primates, items were collected from primers 5Ј-TGTCAGACAAAACGCTGTTC-3Ј (forward) and 5Ј-TGTGGCTTTA- the DAS (19), a frequently used assessment of the quality of marital relation- AAAGTTATCCAG-3Ј (reverse), the RS3 repeat polymorphism was amplified Ј Ј Ј ships and similar dyads, the Support Seeking and Giving (SSG) (26) assessment with primers 5 -TCCTGTAGAGATGTAAGTGC-3 (forward) and 5 -gtttcttTCT- Ј measuring subjects’ engagement with other people, and the Marital Instabil- GGAAGAGACTTAGATGG-3 (reverse) (11, 12, 17), and the RS1 repeat poly- Ј Ј ity Scale (MIS) (27). Partner specific affiliative interaction was measured by the morphism was amplified with primers 5 -AGGGACTGGTTCTACAATCTGC-3 Ј Ј occurrence of partner exclusive actions (for example, ‘‘How often do you kiss (forward) and 5 -ACCTCTCAAGTTATGTTGGTGG-3 (reverse) (11, 12). The fluo- your mate?’’). Proximity measures, which in nonhuman primates are mea- rescently labeled DNA fragments were analyzed by size with automated sured as the amount of spatial closeness between two individuals, were capillary electrophoresis by using an ABI PRISM 3730 Genetic Analyzer (Ap- assessed by two types of items: The proband’s experiences of closeness to plied Biosystems). other people (for example, ‘‘I don’t like when other people come too close to me’’) and items concerning the proband’s motivation to spend time together Statistical Analysis. Statistical associations between the continuous and cate- with their spouse (for example, ‘‘How often are you and your partner involved gorical predictors on the one hand and continuous and binary criteria on the in common interests outside the family?’’). Because one requirement for other were estimated by using Generalized Linear Mixed Effects Models inclusion in the TOSS dataset was that the adult individuals were part of a (GLMM). As earlier studies have shown that the effects of vasopressin on dyadic relationship that had persisted for at least five years, no information pair-bonding behavior differ between sexes (20), all analyses were performed for men and women separately. about the final length of the pair-bonds were available. Instead the proband’s To take the correlated data structure into account and to avoid estimation reports of their attitudes toward the stability of the relationship (for example, problems, different variance-covariance matrices were modeled for monozy- ‘‘Have you discussed a divorce or separation with a close friend?’’) were used gotic twins, spouses to monozygotic twins, dizygotic twins, and spouses to as individual indicators of future persistence of the relationship. No relevant dizygotic twins. Each of these four groups had a cluster size of n ϭ 2. The measures of reciprocity could be found in the TOSS dataset. Thus, of a total of correlations between individuals in these groups were calculated by using 49 items, 18 questions (7 DAS, 10 SSG, and 1 MIS) were considered relevant R-side random effects with an unstructured variance-covariance matrix. The measures of human pair-bonding. A factor analysis was performed, and items model for continuous outcomes assumed normal distribution of residuals with with loadings Ͻ0.4 on the first principal component were excluded [see an identity link function between the predictor term and the criterion. Di- supporting information (SI) Table S1] resulting in the final PBS, which were chotomous outcomes were assumed to be binary distributed with a logit link created as the sum of 13 items (7 DAS, 5 SSG, and 1 MIS), with scores ranging function. The parameters were estimated based on the residual log pseudo- from 5 to 66. The reliability, as measured with Cronbach’s alpha, was 0.79. likelihood (RSPL), which is equivalent to restricted maximum likelihood (31). Validity estimates of the PBS and the original subscales of the validated All statistical analysis was performed by using the Statistical Analysis System questionnaires showed plausible patterns of moderate to high correlation (SAS), Version 9.1.3 (32), and generalized linear mixed effects models were ϭ coefficients (r .40–.75). These results were confirmed by our findings on implemented by using the PROC GLIMMIX procedure. known-groups validity, which showed significant differences between mar- ried and nonmarried subjects (F ϭ 28.28, P Ͻ 0.0001), with nonmarried 1,105 ACKNOWLEDGMENTS. This project was supported by National Institute of subjects scoring lower on the PBS. We also observed that subjects that had Mental Health Grant R01MH54610, Bank of Sweden Tercentenary Foundation experienced during the last year marital crisis/threat of divorce scored signif- Grant J2004–0036:1, and a postdoctoral fellowship sponsored by the Brain icantly lower on the PBS than those who had not (F1,162 ϭ 186.22, P Ͻ 0.0001). Foundation, Sweden (to L.W.).

1. Dunbar RI, Shultz S (2007) Evolution in the social brain. Science 317:1344–1347. 16. Neiderhiser JM, et al. (2007) Father-adolescent relationships and the role of genotype- 2. Young LJ, Wang Z (2004) The neurobiology of pair bonding. Nat Neurosci 7:1048–1054. environment correlation. J Fam Psychol 21:560–571. 3. Cho MM, DeVries AC, Williams JR, Carter CS (1999) The effects of oxytocin and 17. Meyer-Lindenberg A, et al. (2008) Genetic variants in AVPR1A linked to autism predict vasopressin on partner preferences in male and female prairie voles (Microtus ochro- amygdala activation and personality traits in healthy humans. Mol Psychiatry, epub gaster). Behav Neurosci 113:1071–1079. ahead of print. 4. Insel TR, Wang ZX, Ferris CF (1994) Patterns of brain vasopressin receptor distribution 18. Holmes TH, Rahe RH (1967) The Social Readjustment Rating Scale. J Psychosomatic Res associated with social organization in microtine rodents. J Neurosci 14:5381–5392. 11:213–218. 5. Ophir AG, Wolff JO, Phelps SM (2008) Variation in neural V1aR predicts sexual fidelity 19. Spanier GB (1976) Measuring Dyadic Adjustment: New scales for Assessing the Quality and space use among male prairie voles in semi-natural settings. Proc Natl Acad Sci USA of Marriage and Similar Dyads. J Marr Fam 38:15–28. 105:1249–1254. 20. Winslow JT, et al. (1993) A role for central vasopressin in pair bonding in monogamous 6. Lim MM, et al. (2004) Enhanced partner preference in a promiscuous species by prairie voles. Nature 365:545–548. manipulating the expression of a single gene. Nature 429:754–757. 21. Fuentes A (2002) Patterns and Trends in Primate Pair Bonds. Internat J Primatol 7. Young LJ, et al. (1999) Increased affiliative response to vasopressin in mice expressing 23:1573–8604. the V1a receptor from a monogamous vole. Nature 400:766–768. 22. Krebs JR, Davies NB (1997) Behavioral Ecology (Blackwell, London). 8. Hammock EA, Young LJ (2002) Variation in the vasopressin V1a receptor promoter and 23. Fuentes A (2000) Hylobatid communities: Changing views on pair bonding and social expression: Implications for inter- and intraspecific variation in social behaviour. Eur organization in hominoids. Am J Phys Anthropol 43:33–60. J Neurosci 16:399–402. 24. Hinde RA (1983) Primate Social Relationships: An Integrated Approach (Blackwell, 9. Thibonnier M, et al. (1996) Structure, sequence, expression, and chromosomal local- Oxford). ization of the human V1a vasopressin receptor gene. Genomics 31:327–334. 25. Rasmussen DR (1981) Pair-bond strength and stability and reproductive success. Psy- 10. Thibonnier M, et al. (2000) Study of V(1)-vascular vasopressin receptor gene microsat- cholog Rev 88:274–290. ellite polymorphisms in human essential hypertension. J Mol Cell Cardiol 32:557–564. 26. Simpson JA (1990) Influence of attachment styles on romantic relationships. J Person 11. Kim SJ, et al. (2002) Transmission disequilibrium testing of arginine vasopressin recep- tor 1A (AVPR1A) polymorphisms in autism. Mol Psychiatry 7:503–507. Soc Psychol 59:971–980. 12. Wassink TH, et al. (2004) Examination of AVPR1a as an autism susceptibility gene. Mol 27. Booth A, Johnson D, Edwards JN (1983) Measuring Marital Instability. J Marr Fam Psychiatry 9:968–972. 45:387–394. 13. Yirmiya N, et al. (2006) Association between the arginine vasopressin 1a receptor 28. Falconer DS, Mackay TF (1996) Introduction to Quantitative Genetics. (Longman, (AVPR1a) gene and autism in a family-based study: Mediation by socialization skills. Harlow). Mol Psychiatry 11:488–494. 29. Spotts EL, et al. (2004) Genetic and environmental influences on marital relationships. 14. Prichard ZM, Mackinnon AJ, Jorm AF, Easteal S (2007) AVPR1A and OXTR polymor- J Fam Psychol 18:107–119. phisms are associated with sexual and reproductive behavioral phenotypes in humans. 30. Jockin V, McGue M, Lykken DT (1996) Personality and divorce: A genetic analysis. J Pers Mutation in brief no. 981 Online Hum Mutat 28:1150. Soc Psychol 71:288–299. 15. Knafo A, et al. (2007) Individual differences in allocation of funds in the dictator game 31. SAS Institute, Inc. (2006) The GLIMMIX Procedure (Sas Institute, Cary, NC). Available associated with length of the arginine vasopressin 1a receptor RS3 promoter region and from http://support.sas.com/rnd/app/da/glimmix.html. Accessed January 7, 2008. correlation between RS3 length and hippocampal mRNA. Genes Brain Behav 7:266–275. 32. SAS Institute Inc. (2007) SAS/STAT Software (Version 9.1.3) (SAS Institute, Cary, NC).

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